Abstract: Heart failure is a rapidly expanding global pandemic where patient management largely relies on palliative approaches limited to treatment of symptoms, yet is unable to replace diseased tissue. Recent recognition that the heart is continuously undergoing rejuvenation provides a paradigm shift in which cardiac performance is dependent on the net balance of tissue turnover, offering the vision of disease reversibility. The innovative hypothesis of this proposal is that the regenerative potential is imprinted within developmental stem cell signatures, and amenable to reprogramming. The objectives are to stratify individual cardiogenic stem cell load in patients with familial dilated cardiomyopathy, and define innate deficiencies of cardiac repair in order to match regenerative demand. The deliverable is a personalized regenerative algorithm that enables personalized therapy to maximize regenerative outcomes using stem cell-based interventions. Central to the success of the project is the convergence of an original theragnostic strategy, whereby patient-specific cardiogenesis and innate regenerative potential are quantified using induced pluripotent stem cell readouts from patients within the established Mayo Clinic registry of familial dilated cardiomyopathy. The uniqueness of this novel strategy lies in the ability to reveal the identity of pathways that are inherently corrupted, independent of confounding and compensatory variables that are erased by nuclear reprogramming. Resolved disease-causing mutations provide the genotype/phenotype specificity needed to validate the diagnostic criteria and therapeutic metrics of functional regeneration innate to patient-specific induced pluripotent stem cells. The impact of this NIH Directors Innovative Award application expands next- generation stem cell-based theragnostics to advance personalized regenerative medicine beyond the armamentarium available today. ) Public Health Relevance: The proposed project focuses on developing an understanding of how the heart muscle is able to repair itself after an injury. By bioengineering stem cells from the patient's body, this study will characterize the ability of stem cells to differentiate into heart muscle and repair damaged heart muscle. This work will have broad impact on the development of novel strategies to diagnose and treat patients with heart failure.